Project Summary Human vision operates over a billion-fold range of light intensities ranging from starlight to bright daylight, with night vision subserved by retinal rod photoreceptor cells, and day vision by cone photoreceptor cells. Rods and cones mediate the first steps in vision by capturing light in their G-protein coupled receptors Rhodopsin, and L/M and S-cone opsins, respectively, whose activation then generates electrical responses through homologous G-protein-coupled receptor signaling cascades. While the molecular mechanisms that underlie the rod's ability to signal in dim light are now well understood, the mechanisms that enable some cones (but not rods) to function in bright daylight are relatively poorly understood. Using non-invasive optical and electroretinographic methodology applicable to humans, the proposed work proposed will investigate cone and rod function in vivo under daylight conditions, testing hypotheses about the mechanisms that allow cones expressing only M-opsin to operate in bright light, while cones expressing only S-opsin, and rods do not, and to understand how the very abundant, non- signaling rods cope with the enormous stress that daylight makes on their molecular machinery. Among key resources for the project are cone-monochromat mice created by the author and his collaborators, which only express one cone opsin, and adaptive-optics (AO) optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) customized and calibrated for precisely controlling the quantity of light captured by each of the mouse opsins. The work in this project addresses a fundamental need for in vivo studies of cone and rod function in daylight conditions, to establish cellular and molecular mechanistic foundations that support and interpret the signal advances in AO imaging of human cones and rods.